Recent development in analytical technology has made possible the fast determination of unit content in a large number of dosage units from a batch using nondestructive analytical methods during production. These measurement techniques are often referred to as process analytical technology (PAT). Using such methodology, a better understanding of the manufacturing process, in line with the quality-by-design (QbD) concept according to the International Conference on Harmonization (ICH) Quality Guidelines Q8–Q11, and a closer control of the drug product can be obtained compared with the use of traditional analytical methods. The increased process control that is achieved by PAT is attractive both from the patient's point of view (improved product quality) and from the industry's point of view (increased production efficacy, less batch rejection).

M. Horvat

Acceptable batch quality is demonstrated by compliance with the drug product specification. Usually, several of the tests of a specification refer to pharmacopeial test methodologies and acceptance criteria. One such test is the European Pharmacopoeia (Ph.Eur.) General Chapter 2.9.40 on Uniformity of Dosage Units (UDU). To take full advantage of the increased batch control that is gained by PAT in general and large sample size in particular, there has been a demand for a test method that utilizes large sample sizes to demonstrate compliance with UDU. Such a test has recently been adopted by the European Pharmacopoeia Commission, and will be published as Ph.Eur. General Chapter 2.9.47. In this paper, the new test is presented and explained.

Background

To ensure the consistency of dosage units, each unit in a batch should have an active substance content within a limited range around the label claim (1). Ph.Eur. General Chapter 2.9.40 on UDU addresses the recommended test to demonstrate this critical property in a batch of drug product. The general monograph was introduced in Supplement 5.2 of the Ph.Eur., and is harmonized with the Japanese Pharmacopeia (JP). The test is also included in the US Pharmacopeia (USP), but with a reservation against the possibility to demonstrate UDU by mass variation rather than content uniformity, which is allowed in Ph.Eur. and JP under certain circumstances (2). When justified and authorized, acceptable dose uniformity may be demonstrated by compliance with Ph.Eur. General Chapter 2.9.5 Uniformity of Mass of Single-Dose Preparations (2.9.5) or General Chapter 2.9.6 Uniformity of Content of Single-Dose Preparations (2.9.6) instead of the UDU test (3).

With the harmonized UDU test, acceptable and nonacceptable batches, respectively, are more precisely judged than with the 2.9.5/2.9.6 tests, as the sample size is larger (n = 30, as opposed to n = 20, and n = 10, respectively). The UDU test returns a numerical measure of the dose consistency—that is, the acceptance value (AV). In addition, UDU takes into account sample mean: a stricter standard deviation requirement applies if the sample mean is more than 1.5% off-target. The performance of the old and the new General Chapters has been discussed by Limberg and Savsek (4).

Although it is assumed that the sample is representative for the batch, it is acknowledged that the evaluation of a small sample will only provide an estimate of the batch quality. There is always a risk that a highly variable batch would pass the UDU test and be released. Likewise, there is always a risk that a good quality batch can fail the UDU test and be rejected. Increasing the sample size leads to a more precise estimate of the batch variability.

Concerns have been raised that the UDU requirements discourage the use of modern analytical techniques that are fast and nondestructive (e.g., PAT techniques) (5–10). It was unfortunate that a pharmacopoeial requirement could be regarded as a disincentive to the implementation of such analytical methods.

The main concern with the UDU test when applied to large samples was the requirement that no single result of the test sample is outside ± L2 % of the reference value M (M = "sample average"; L2 = 25.0, unless otherwise specified. For a precise definition of M, refer to Ph.Eur. 2.9.40). Such an unconditional requirement is included in both General Chapters 2.9.5/2.9.6 and the UDU chapter. The requirement was established to disclose batches with largely deviating units, even if the sample mean and the overall sample variance is acceptable. This "safety net" does not assume any distribution in the sample or in the batch (e.g., normality), and it seems reasonable enough not to allow any largely deviating unit in a small sample.

Even in normal distributed batches of good quality, a small number of largely deviating units is expected. As sample size increases, the probability to detect one of these units becomes significant. In the new General Chapter 2.9.47 (2.9.47), a small number of largely deviating units is allowed for large sample sizes. This allowance is not considered an acceptance of largely deviating units as such, but rather recognizes that the large sample has a greater probability to contain such units, even when the batch in total is considered to be of acceptable quality.

A proposal for 2.9.47 was published in Pharmeuropa 23.2 in March 2011, together with a background paper explaining the elaboration of the proposal in detail (9). During the public consultation period, several comments were submitted by industry and regulators. The feedback was fairly uniform, and the European Directorate for the Quality of Medicines (EDQM) PAT working party accordingly elaborated a revised proposal for Chapter 2.9.47. The revised text was adopted by the European Pharmacopoeia Commission in April 2012, and it will be published in Supplement 7.7 of the Ph.Eur. and implemented on Apr. 1, 2013.